JPH0819039B2 - New bioactive substance derived from propolis - Google Patents
New bioactive substance derived from propolisInfo
- Publication number
- JPH0819039B2 JPH0819039B2 JP3219021A JP21902191A JPH0819039B2 JP H0819039 B2 JPH0819039 B2 JP H0819039B2 JP 3219021 A JP3219021 A JP 3219021A JP 21902191 A JP21902191 A JP 21902191A JP H0819039 B2 JPH0819039 B2 JP H0819039B2
- Authority
- JP
- Japan
- Prior art keywords
- propolis
- bioactive substance
- substance derived
- new bioactive
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
【発明の詳細な説明】Detailed Description of the Invention
【０００１】[0001]
【産業上の利用分野】本発明はプロポリス由来新生理活
性物質に関する。プロポリス由来新生理活性物質は、抗
腫瘍作用を有し、抗腫瘍剤として有用である。TECHNICAL FIELD The present invention relates to a novel bioactive substance derived from propolis. The new bioactive substance derived from propolis has an antitumor effect and is useful as an antitumor agent.
【０００２】[0002]
【従来の技術】プロポリスはミツバチが採取した樹脂類
と唾液分泌物、蜜蝋、花粉などとが混合された一種のに
かわ質で、抗菌、抗炎症をはじめとする様々な薬理作用
を持つ民間薬として知られている。プロポリスのエタノ
ール抽出物が抗腫瘍作用を有することは知られている
〔ツァィトシュリフト・フュア・ナチュアフォルシュン
グ(Z. Naturforsch.) C 44,1063, (1989)〕。2. Description of the Related Art Propolis is a kind of glue that is a mixture of resins collected by honeybees with salivary secretions, beeswax, pollen, etc., and is a folk medicine with various pharmacological actions including antibacterial and anti-inflammatory. Are known. It is known that the ethanol extract of propolis has an antitumor effect [Z. Naturforsch. C 44 , 1063, (1989)].
【０００３】また式（ＩＩ）Also, the formula (II)
【０００４】[0004]
【化２】 Embedded image
【０００５】で表されるプロポリスの一成分であるカフ
ェイン酸フェネチルエステルが抗腫瘍作用を有すること
は知られている〔エクスペリエンティア(Experientia)
44, 230, (1988) 〕。抗腫瘍作用を有するプロポリス抽
出物の製造法は本発明者らにより開示されている（特願
平３−１６２５９６）。It is known that caffeic acid phenethyl ester, which is a component of propolis represented by, has an antitumor effect [Experientia]
44 , 230, (1988)]. A method for producing a propolis extract having an antitumor action has been disclosed by the present inventors (Japanese Patent Application No. Hei 3-162596).
【０００６】また、本発明の化合物に類似した骨格を有
する化合物としては、例えば下記式で示される化合物が
知られている。 式（ＩＩＩ）Further, as a compound having a skeleton similar to that of the compound of the present invention, for example, a compound represented by the following formula is known. Formula (III)
【０００７】[0007]
【化３】 Embedded image
【０００８】で表されるボリビアノール〔ボレティン・
デ・ラ・ソシエダ・チレナ・デ・キミカ（Bol. Soc. Ch
il. Quim. ）35, 257,(1990) (ケミカルアブストラクト
114 ,39206u）〕、 式（ＩＶ）Bolivianol represented by [Boletin
De La Socieda Chilena de Kimika (Bol. Soc. Ch
il. Quim.) 35 , 257, (1990) (Chemical Abstract
114, 39206u)], the formula (IV)
【０００９】[0009]
【化４】 [Chemical 4]
【００１０】（式中、ＸおよびＹは同一にCH2OH または
異なってCH2OH またはH を表す)で表される化合物〔フ
ァィトケミストリー（Phytochemistry）28, 531, 3415
(1989)〕、 式（Ｖ）[Wherein X and Y are the same CH 2 OH or differently CH 2 OH or H] [Phytochemistry 28 , 531, 3415]
(1989)], formula (V)
【００１１】[0011]
【化５】 Embedded image
【００１２】で表される化合物〔ファィトケミストリー
（Phytochemistry）28, 3415, 2507(1989)〕、 式（ＶＩ）A compound represented by the formula [Phytochemistry 28 , 3415, 2507 (1989)], formula (VI)
【００１３】[0013]
【化６】 [Chemical 6]
【００１４】で表される化合物〔ファィトケミストリー
（Phytochemistry）20, 1657(1981)〕。しかし、これら
の化合物の抗腫瘍作用に関する報告はない。A compound represented by the formula [Phytochemistry 20 , 1657 (1981)]. However, there are no reports on the antitumor effect of these compounds.
【００１５】[0015]
【発明が解決しようとする課題】本発明の目的は、優れ
た抗腫瘍作用を有する化合物を提供することにある。An object of the present invention is to provide a compound having an excellent antitumor action.
【００１６】[0016]
【課題を解決するための手段】本発明者らは、プロポリ
ス中に抗腫瘍作用を有する物質が存在することを見出し
た。この物質を単離、精製し、その理化学的性質を調べ
た結果、新規物質であることが判明し、プロポリス由来
新生理活性物質と命名した。本発明によれば、式（Ｉ）The present inventors have found that there is a substance having an antitumor effect in propolis. As a result of isolating and purifying this substance and examining its physicochemical properties, it was found to be a novel substance, and it was named a new bioactive substance derived from propolis. According to the invention, the formula (I)
【００１７】[0017]
【化７】 [Chemical 7]
【００１８】で表されるプロポリス由来新生理活性物質
を提供する。以下に本発明を詳細に説明する。プロポリ
ス由来新生理活性物質の理化学的性質を以下に示す。 (i) 分子量：320 (ii)分子式：Ｃ20Ｈ32Ｏ3 (iii) 質量分析：SIMS法（マトリックスにグリセロール
使用）：m/z 321(M+H)+ 高分解能SIMSスペクトル：321.2403 Ｃ20Ｈ33Ｏ3 としての計算値：321.2430 (iv)比旋光度：〔α〕D 25 =−83°（c=0.44, メタノー
ル） (v) 紫外部吸収スペクトル：（メタノール中） λmax：212nm （ε=4,600), 288nm（ε=2,600） (vi)赤外部吸収スペクトル：（KBr 錠剤法） ν(cm -1):3600〜2400, 3450, 2941, 1695, 1641, 143
9, 1385, 1259 (vii)1H-NMR ：（500MHz, ＣＤ3 ＯＤ）内部基準ＴＭＳ δ(ppm): 5.63(1H, br.s), 5.18(1H, m), 3.84(1H, dd,
J=10.6, 3.1Hz), 3.21(1H, br.t), 1.89(3H, d, J=1.3
Hz), 1.58(3H, d, J=1.3Hz), 1.03(3H, s), 0.75(3H,
s) (viii)13C-NMR ：（125MHz, ＣＤ3 ＯＤ）内部基準ＴＭ
Ｓ δ(ppm): 170.4, 161.7, 145.1, 121.8, 117.7, 64.4,
47.9, 45.5, 39.4, 39.2, 37.7, 37.6, 28.4, 27.7, 2
5.4, 23.2, 20.3, 19.5, 18.8, 18.2 (ｉｘ)溶解性：メタノール、酢酸エチル、クロロホル
ム、ＤＭＳＯに可溶、酸性水には難溶。 (x) 呈色反応：ヨード試薬、ＢＣＧ試薬、硫酸セリウム
試薬に陽性。 (xi)性状：無色の固体。 (xii) 高速液体クロマトグラフィー：逆相シリカゲル系
充填剤 カラム：ＹＭＣ社製 ＡＭ− 312 （ＯＤＳ、球状、５
μｍ、細孔径６０オングストローム、６.0ｍｍφ×１５
０ｍｍ）； 溶離液：０．０２Ｍ 酢酸ー酢酸アンモニ
ウム（ｐＨ５.0）−メタノール〔２５：７５（ｖ/
ｖ）〕；流速１ｍｌ／ｍｉｎ；検出：２４０ｎｍ紫外部
吸収により検出；保持時間：１６.7分。A novel bioactive substance derived from propolis represented by the following is provided. The present invention will be described in detail below. The physicochemical properties of the new bioactive substance derived from propolis are shown below. (i) Molecular weight: 320 (ii) Molecular formula: C 20 H 32 O 3 (iii) Mass analysis: SIMS method (using glycerol as matrix): m / z 321 (M + H) + high resolution SIMS spectrum: 321.2403 C 20 Calculated as H 33 O 3 : 321.2430 (iv) Specific rotation: [α] D 25 = −83 ° (c = 0.44, methanol) (v) Ultraviolet absorption spectrum: (in methanol) λmax: 212 nm (ε = 4,600), 288nm (ε = 2,600) (vi) Infrared absorption spectrum: (KBr tablet method) ν (cm -1 ): 3600 ~ 2400, 3450, 2941, 1695, 1641, 143
9, 1385, 1259 (vii) 1 H-NMR: (500MHz, CD 3 OD) Internal standard TMS δ (ppm): 5.63 (1H, br.s), 5.18 (1H, m), 3.84 (1H, dd,
J = 10.6, 3.1Hz), 3.21 (1H, br.t), 1.89 (3H, d, J = 1.3
Hz), 1.58 (3H, d, J = 1.3Hz), 1.03 (3H, s), 0.75 (3H,
s) (viii) 13 C-NMR: (125MHz, CD 3 OD) Internal reference TM
S δ (ppm): 170.4, 161.7, 145.1, 121.8, 117.7, 64.4,
47.9, 45.5, 39.4, 39.2, 37.7, 37.6, 28.4, 27.7, 2
5.4, 23.2, 20.3, 19.5, 18.8, 18.2 (ix) Solubility: Soluble in methanol, ethyl acetate, chloroform and DMSO, hardly soluble in acidic water. (x) Color reaction: Positive with iodine reagent, BCG reagent, and cerium sulfate reagent. (xi) Property: Colorless solid. (xii) High performance liquid chromatography: Reversed phase silica gel-based packing material Column: YMC AM-312 (ODS, spherical, 5
μm, pore size 60 Å, 6.0 mmφ × 15
Eluent: 0.02M acetic acid-ammonium acetate (pH 5.0) -methanol [25:75 (v /
v)]; flow rate 1 ml / min; detection: detected by UV absorption at 240 nm; retention time: 16.7 minutes.
【００１９】次にプロポリス由来新生理活性物質の生物
活性について説明する。 ＨｅＬａ Ｓ3 細胞に対する生育阻害 ９６穴マイクロタイタープレートの各穴に、10％牛胎児
血清および２mMグルタミンを含むMEM 培地により適宜希
釈した試験化合物0.1ml ずつ添加後、トリプシン処理し
たHeLa S3細胞(ATCC HTB22)を上記培養液で3 ×104 個
／mlに調製し、0.05mlずつ分注した。Next, the biological activity of the new bioactive substance derived from propolis will be described. Growth inhibition on HeLa S3 cells HeLa S3 cells (ATCC HTB22) treated with trypsin after adding 0.1 ml of each test compound appropriately diluted with MEM medium containing 10% fetal bovine serum and 2 mM glutamine to each well of a 96-well microtiter plate. Was prepared at 3 × 10 4 cells / ml with the above-mentioned culture solution and dispensed in 0.05 ml portions.
【００２０】該プレートを炭酸ガスインキュベータ内で
37℃、72時間培養後、培養上清を除去し、0.02% ニュー
トラルレッドを含む培養液を0.1 mlずつ各穴に加え、37
℃で1時間炭酸ガスインキュベータ内で培養し、細胞を
染色した。培養上清を除去後、残渣を生理食塩水で１回
洗浄した。ついで0.001 規定塩酸／30％エタノールで色
素を抽出後、マイクロプレートリーダーにより 550nmの
吸光度を測定した。無処理細胞と既知濃度の試験化合物
で処理した細胞の吸光度を比較して次式に従って細胞の
増殖阻止率を算出した。The plate is placed in a carbon dioxide incubator
After culturing at 37 ℃ for 72 hours, remove the culture supernatant and add 0.1 ml of culture solution containing 0.02% Neutral Red to each well.
The cells were stained by culturing in a carbon dioxide gas incubator at 0 ° C for 1 hour. After removing the culture supernatant, the residue was washed once with physiological saline. Then, the dye was extracted with 0.001 N hydrochloric acid / 30% ethanol, and the absorbance at 550 nm was measured with a microplate reader. The absorbance of untreated cells and cells treated with a test compound at a known concentration were compared to calculate the cell growth inhibition rate according to the following formula.
【００２１】[0021]
【数１】 [Equation 1]
【００２２】得られた増殖阻止率から、細胞の増殖を50
％阻害する試験化合物濃度(IC50)を算出した。その結果
を第１表に示す。From the obtained growth inhibition rate, the cell growth was determined to be 50
The concentration of test compound that inhibits% (IC 50 ) was calculated. The results are shown in Table 1.
【００２３】[0023]
【表１】 [Table 1]
【００２４】細胞周期をフローサイトメーターにて解析
した結果、試験化合物は、増殖細胞をＳ期で停止させる
とともに、これを死滅させることが明かとなった。以上
のようにプロポリス由来新生理活性物質は培養腫瘍細胞
に対し抗腫瘍活性を示し抗腫瘍剤として有用である。次
にプロポリス由来新生理活性物質の製造法について説明
する。プロポリスより本発明の化合物を含む抽出物の製
造法の一例を参考例にあげる。抽出物からプロポリス由
来新生理活性物質の単離精製は、常用される方法、例え
ば高速液体クロマトグラフィーなどに従って行われる。
なお、精製工程中のプロポリス由来新生理活性物質の動
向は、紫外部吸収により追跡することができる。As a result of analyzing the cell cycle by a flow cytometer, it was revealed that the test compound stops the proliferating cells at the S phase and kills them. As described above, the new bioactive substance derived from propolis exhibits antitumor activity against cultured tumor cells and is useful as an antitumor agent. Next, a method for producing a new bioactive substance derived from propolis will be described. An example of a method for producing an extract containing the compound of the present invention from propolis is given as a reference example. Isolation and purification of the propolis-derived new physiologically active substance from the extract is performed according to a commonly used method, for example, high performance liquid chromatography.
The trend of the new bioactive substance derived from propolis during the purification step can be traced by ultraviolet absorption.
【００２５】以下に本発明の実施例を示す。なお、プロ
ポリス由来新生理活性物質の物理化学的データは以下の
機器により測定した。 マススペクトル： 日立製作所社製 M - 80B 質量分析装置 日本電子社製 SX - 102質量分析装置 旋光度： 日本分光社製 DIP - 370 分光計 紫外部吸収スペクトル： 島津製作所社製 UV - 2200 分光光度計 赤外部吸収スペクトル： 日本電子社製 JIR - RFX3001 赤外線分光光度計 ＮＭＲスペクトル： ブルカー社製 AM500 核磁気共鳴装置Examples of the present invention will be shown below. The physicochemical data of the new bioactive substance derived from propolis was measured by the following equipment. Mass spectrum: Hitachi M-80B mass spectrometer JEOL SX-102 mass spectrometer Optical rotation: JASCO DIP-370 spectrometer UV absorption spectrum: Shimadzu UV-2200 spectrophotometer Red External absorption spectrum: JIR-RFX3001 infrared spectrophotometer NMR spectrum manufactured by JEOL Ltd. AM500 nuclear magnetic resonance instrument manufactured by Bruker
【００２６】[0026]
【実施例】実施例１.参考例によって得られた酸性アセ
トニトリルを用いた分取画分２ｍｇをメタノールに溶解
し、高速液体クロマトグラフィー用ＯＤＳ系カラム〔Ｙ
ＭＣ ＳＨ 345 - 5、ワイエムシィ（株）社製 〕で精
製した〔溶出条件：７５％（Ｖ／Ｖ）メチルアルコール
−20mM酢酸アンモニウム，pH5.0 流速10ml／分〕。保持
時間４９〜５１分に紫外線（波長240ｎｍ）を吸収する
画分を得た。上記の操作を繰り返し、得られた画分より
減圧下メチルアルコールを留去した。水溶液に１／１０
容の１規定塩酸を加え、酢酸エチルにて抽出した。常法
に従い有機層を飽和食塩水にて洗浄後、無水硫酸ナトリ
ウムにて乾燥した。有機溶媒を減圧下留去しプロポリス
由来新生理活性物質を無色固体として４. ４ｍｇ得た。EXAMPLES Example 1. 2 mg of a preparative fraction obtained by using the acidic acetonitrile obtained in Reference Example was dissolved in methanol, and the ODS column for high performance liquid chromatography [Y
MC SH 345-5, manufactured by YMC Co., Ltd.] [elution condition: 75% (V / V) methyl alcohol-20 mM ammonium acetate, pH 5.0, flow rate 10 ml / min]. A fraction absorbing ultraviolet rays (wavelength 240 nm) was obtained at a retention time of 49 to 51 minutes. The above operation was repeated, and methyl alcohol was distilled off from the obtained fraction under reduced pressure. 1/10 in aqueous solution
1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate according to a conventional method. The organic solvent was distilled off under reduced pressure to obtain 4.4 mg of a new bioactive substance derived from propolis as a colorless solid.
【００２７】プロポリス由来新生理活性物質の理化学的
性質および構造は前記のとおりである。 実施例２． 参考例によって得られたエチルアルコールを用いた分取
画分より実施例１と同様な操作を行って本発明のプロポ
リス由来新生理活性物質を得た。The physicochemical properties and structure of the new bioactive substance derived from propolis are as described above. Embodiment 2. FIG. The propolis-derived novel physiologically active substance of the present invention was obtained by performing the same operation as in Example 1 from the fractionated fraction using ethyl alcohol obtained in Reference Example.
【００２８】参考例 ブラジル産プロポリス１００ｇを１０倍量（Ｖ／Ｖ）の
９９.５％（Ｗ／Ｗ）エチルアルコールと混合し、室温
下攪拌した。得られた懸濁液を濾紙を通して減圧濾過し
て、プロポリスのエチルアルコール抽出液を得た。次い
で、得られたエチルアルコール抽出液の溶媒を減圧下留
去し、得られた残渣３０ｇを水と酢酸エチルとの１：１
混液に溶解し、有機層に抽出することによりプロポリス
の酢酸エチル抽出液を得た。得られた抽出液の溶媒を減
圧下留去し、得られた残渣２０ｇを９９. ５％（Ｗ／
Ｗ）メチルアルコールで溶解し、不溶物を遠心分離によ
り除去して、メチルアルコール抽出液を得た。得られた
メチルアルコール抽出液を、７０％（Ｖ／Ｖ）酸性メチ
ルアルコール（ｐＨを酢酸で３. ５に調整したもの）で
平衡化した高速液体クロマトグラフィー用ＯＤＳ系カラ
ム〔東ソーＯＤＳ ８０ＴＭ、東ソー（株）社製 〕で
精製した〔溶出条件：アセトニトリル７０から１００％
（Ｖ／Ｖ），ｐＨ３．５〕。この後、酸性メチルアルコ
ール濃度８２から８８％（Ｖ／Ｖ）の画分を集めた。得
られた画分を１つにまとめ、溶媒を減圧下留去して残渣
２００ｍｇを得た。次いで、得られた残渣を７０％（Ｖ
／Ｖ）酸性アセトニトリル（ｐＨを酢酸で３. ５に調整
したもの）に溶解させ、得られた溶液を、７０％（Ｖ／
Ｖ）酸性アセトニトリル（ｐＨを酢酸で３. 5 に調整し
たもの）で平衡化した高速液体クロマトグラフィー用Ｏ
ＤＳ系カラム〔東ソーＯＤＳ ８０ＴＭ、東ソー（株）
社製 〕で精製した〔溶出条件：アセトニトリル７０か
ら１００％（Ｖ／Ｖ），ｐＨ３．５〕。この後、酸性ア
セトニトリル濃度７３〜７６％の画分を集めた。得られ
た画分を１つにまとめ、溶媒を減圧下留去して残渣５０
ｍｇを得た。次いで、得られた残渣を７０％（Ｖ／Ｖ）
アセトニトリルに溶解させ、得られた溶液を、７５％
（Ｖ／Ｖ）エチルアルコールで平衡化した高速液体クロ
マトグラフィー用ＯＤＳ系カラム〔東ソーＯＤＳ ８０
ＴＭ、東ソー（株）社製〕で精製した〔溶出条件：エチ
ルアルコール７５から９０％（Ｖ／Ｖ）〕。この後、エ
チルアルコール濃度８０〜８５％の画分を集めた。紫外
線（波長２５４ｎｍ）を吸収する主画分のうち後方の画
分を集めて、プロポリス抽出物を得た。Reference Example 100 g of Brazilian propolis was mixed with 10-fold amount (V / V) of 99.5% (W / W) ethyl alcohol and stirred at room temperature. The resulting suspension was filtered under reduced pressure through filter paper to obtain an ethyl alcohol extract of propolis. Then, the solvent of the obtained ethyl alcohol extract was distilled off under reduced pressure, and 30 g of the obtained residue was mixed with water and ethyl acetate in a ratio of 1: 1.
It was dissolved in the mixed solution and extracted into the organic layer to obtain an ethyl acetate extract of propolis. The solvent of the obtained extract was distilled off under reduced pressure, and 20 g of the obtained residue was 99.5% (W /
W) It was dissolved in methyl alcohol and the insoluble material was removed by centrifugation to obtain a methyl alcohol extract. The obtained methyl alcohol extract was equilibrated with 70% (V / V) acidic methyl alcohol (pH adjusted to 3.5 with acetic acid) for ODS column for high performance liquid chromatography [Tosoh ODS 80TM, Tosoh. (Manufactured by KK) [Elution condition: acetonitrile 70 to 100%
(V / V), pH 3.5]. Thereafter, fractions having an acidic methyl alcohol concentration of 82 to 88% (V / V) were collected. The obtained fractions were combined and the solvent was distilled off under reduced pressure to obtain 200 mg of a residue. Then, the obtained residue was treated with 70% (V
/ V) Dissolved in acidic acetonitrile (pH adjusted to 3.5 with acetic acid) and the resulting solution was 70% (V /
V) O for high performance liquid chromatography equilibrated with acidic acetonitrile (pH adjusted to 3.5 with acetic acid)
DS column [Tosoh ODS 80TM, Tosoh Corporation
Manufactured by the company) [elution conditions: acetonitrile 70 to 100% (V / V), pH 3.5]. Thereafter, fractions having an acidic acetonitrile concentration of 73 to 76% were collected. The obtained fractions were combined and the solvent was distilled off under reduced pressure to give a residue 50.
mg was obtained. Then, the obtained residue is 70% (V / V)
Dissolve the resulting solution in acetonitrile, 75%
ODS column for high performance liquid chromatography equilibrated with (V / V) ethyl alcohol [TOSO ODS 80
TM, manufactured by Tosoh Corporation] [elution conditions: ethyl alcohol 75 to 90% (V / V)]. Thereafter, a fraction having an ethyl alcohol concentration of 80 to 85% was collected. The rear fractions of the main fractions that absorb ultraviolet rays (wavelength 254 nm) were collected to obtain a propolis extract.
【００２９】[0029]
【発明の効果】本発明により抗腫瘍作用を有する新規プ
ロポリス由来新生理活性物質が提供される。INDUSTRIAL APPLICABILITY The present invention provides a novel bioactive substance derived from a novel propolis having an antitumor effect.
Claims (1)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3219021A JPH0819039B2 (en) | 1991-08-29 | 1991-08-29 | New bioactive substance derived from propolis |
| EP92305326A EP0532156A1 (en) | 1991-08-29 | 1992-06-10 | Physiologically active diterpenoid |
| US07/899,730 US5276177A (en) | 1991-08-29 | 1992-06-17 | Physiologically active substance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3219021A JPH0819039B2 (en) | 1991-08-29 | 1991-08-29 | New bioactive substance derived from propolis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0558943A JPH0558943A (en) | 1993-03-09 |
| JPH0819039B2 true JPH0819039B2 (en) | 1996-02-28 |
Family
ID=16729013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3219021A Expired - Lifetime JPH0819039B2 (en) | 1991-08-29 | 1991-08-29 | New bioactive substance derived from propolis |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US5276177A (en) |
| EP (1) | EP0532156A1 (en) |
| JP (1) | JPH0819039B2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09143179A (en) * | 1995-11-24 | 1997-06-03 | Eiken Chem Co Ltd | Benzopyran derivative derived from propolis |
| JPH09183724A (en) * | 1995-12-29 | 1997-07-15 | Eiken Chem Co Ltd | Naphthalene carboxylic acid derivative |
| AU1785799A (en) * | 1998-01-30 | 1999-08-16 | Ivan Gorgiev | Anticancer composition |
| US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| US6541515B2 (en) * | 2000-08-09 | 2003-04-01 | Merck & Co., Inc. | HIV integrase inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5008441A (en) * | 1987-08-04 | 1991-04-16 | The Trustees Of Columbia University In The City Of New York | Caffeic acid esters and methods of producing and using same |
-
1991
- 1991-08-29 JP JP3219021A patent/JPH0819039B2/en not_active Expired - Lifetime
-
1992
- 1992-06-10 EP EP92305326A patent/EP0532156A1/en not_active Withdrawn
- 1992-06-17 US US07/899,730 patent/US5276177A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0532156A1 (en) | 1993-03-17 |
| US5276177A (en) | 1994-01-04 |
| JPH0558943A (en) | 1993-03-09 |
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